Promoters of ASCL1- and NEUROD1-dependent genes are specific targets of lurbinectedin in SCLC cells.
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Carbolines
/ pharmacology
Cell Line, Tumor
Heterocyclic Compounds, 4 or More Rings
/ pharmacology
Humans
Lung Neoplasms
/ drug therapy
Promoter Regions, Genetic
/ drug effects
Repressor Proteins
/ metabolism
Small Cell Lung Carcinoma
/ drug therapy
ASCL1/NEUROD1
E-boxes/CpG islands
lurbinectedin
transcription addiction
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 04 2022
07 04 2022
Historique:
revised:
16
02
2022
received:
12
07
2021
accepted:
17
02
2022
pubmed:
10
3
2022
medline:
9
4
2022
entrez:
9
3
2022
Statut:
ppublish
Résumé
Small-Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes, SCLC-A and SCLC-N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E-box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according to ATAC and H3K27Ac signatures. This leverage is used by the marine agent lurbinectedin, which preferentially targets the CpG islands located downstream of the transcription start site, thus arresting elongating RNAPII and promoting its degradation. This abrogates the expression of ASCL1 and NEUROD1 and of their dependent genes, such as BCL2, INSM1, MYC, and AURKA, which are responsible for relevant SCLC tumorigenic properties such as inhibition of apoptosis and cell survival, as well as for a part of its neuroendocrine features. In summary, we show how the transcription addiction of these cells becomes their Achilles's heel, and how this is effectively exploited by lurbinectedin as a novel SCLC therapeutic endeavor.
Identifiants
pubmed: 35263037
doi: 10.15252/emmm.202114841
pmc: PMC8988166
doi:
Substances chimiques
ASCL1 protein, human
0
Basic Helix-Loop-Helix Transcription Factors
0
Carbolines
0
Heterocyclic Compounds, 4 or More Rings
0
NEUROD1 protein, human
0
PM 01183
0
Repressor Proteins
0
INSM1 protein, human
147955-03-1
Banques de données
GEO
['GSE179074', 'GSE195663']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14841Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Cancer Cell. 2021 Mar 8;39(3):346-360.e7
pubmed: 33482121
Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6524-9
pubmed: 23553831
Nat Biotechnol. 2020 Mar;38(3):276-278
pubmed: 32055031
Cancer Gene Ther. 2006 Apr;13(4):375-84
pubmed: 16052225
Mol Cancer Ther. 2016 Oct;15(10):2399-2412
pubmed: 27630271
Nat Genet. 2012 Oct;44(10):1104-10
pubmed: 22941188
J Biol Chem. 1997 Mar 14;272(11):7122-6
pubmed: 9054406
Mol Cell. 2010 Apr 9;38(1):54-66
pubmed: 20385089
Annu Rev Biochem. 2016 Jun 2;85:265-90
pubmed: 27294439
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Clin Cancer Res. 2021 May 1;27(9):2378-2382
pubmed: 33288660
J Biol Chem. 2008 Jul 25;283(30):21160-9
pubmed: 18339630
J Med Chem. 2006 Nov 16;49(23):6925-9
pubmed: 17154523
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
Chem Biol. 2011 Aug 26;18(8):988-99
pubmed: 21867914
Cancer Cell. 2014 Dec 8;26(6):909-922
pubmed: 25490451
Cell Rep. 2016 Aug 2;16(5):1259-1272
pubmed: 27452466
Nature. 1997 Apr 24;386(6627):852-5
pubmed: 9126746
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cancer Cell. 2011 Jun 14;19(6):754-64
pubmed: 21665149
Future Oncol. 2021 Jun;17(18):2279-2289
pubmed: 33736462
Cancer Cell. 2014 Dec 8;26(6):783-784
pubmed: 25490443
Nat Biotechnol. 2019 Aug;37(8):907-915
pubmed: 31375807
CA Cancer J Clin. 2021 May;71(3):209-249
pubmed: 33538338
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):
pubmed: 33875598
Genes Dev. 2006 Nov 1;20(21):2922-36
pubmed: 17079683
Mol Cell. 2017 Dec 21;68(6):1054-1066.e6
pubmed: 29225035
Mol Cell. 2004 Oct 22;16(2):187-97
pubmed: 15494306
Nat Rev Cancer. 2019 May;19(5):289-297
pubmed: 30926931
Development. 2000 Sep;127(18):3913-21
pubmed: 10952889
J Biol Chem. 1996 Nov 15;271(46):29238-44
pubmed: 8910583
J Biol Chem. 1994 May 13;269(19):14170-4
pubmed: 8188699
Annu Rev Pharmacol Toxicol. 2001;41:53-77
pubmed: 11264450
Oncoimmunology. 2020 Jul 21;9(1):1795995
pubmed: 32923159
Oncology (Williston Park). 2014 Nov;28(11):945-7
pubmed: 25741544
Oncol Rep. 2014 Jul;32(1):243-9
pubmed: 24841948
Genome Biol. 2008;9(9):R137
pubmed: 18798982
JAMA Oncol. 2019 Dec 1;5(12):1749-1768
pubmed: 31560378
Clin Cancer Res. 2008 Jun 1;14(11):3268-77
pubmed: 18519752
Nat Commun. 2019 May 7;10(1):2084
pubmed: 31064989
Br J Pharmacol. 2010 Nov;161(5):1099-110
pubmed: 20977459
EMBO Mol Med. 2022 Apr 7;14(4):e14841
pubmed: 35263037
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Transl Lung Cancer Res. 2018 Feb;7(1):4-20
pubmed: 29535909
Cancer Res. 2009 Feb 1;69(3):845-54
pubmed: 19176379
Cancers (Basel). 2021 Mar 08;13(5):
pubmed: 33800236
Mol Oncol. 2020 Feb;14(2):277-293
pubmed: 31782890
Nat Rev Clin Oncol. 2017 Sep;14(9):549-561
pubmed: 28534531
Cancer Cell. 2020 Jul 13;38(1):60-78.e12
pubmed: 32473656
J Natl Cancer Inst. 2013 Jul 17;105(14):1059-65
pubmed: 23739064
Transl Lung Cancer Res. 2018 Feb;7(1):50-68
pubmed: 29535912
Cell Cycle. 2017 Aug 18;16(16):1489-1498
pubmed: 28737478
Cancer Biol Ther. 2006 Dec;5(12):1600-7
pubmed: 17224634
N Engl J Med. 2018 Dec 6;379(23):2220-2229
pubmed: 30280641
J Thorac Oncol. 2007 Apr;2(4):327-43
pubmed: 17409807
Mol Cancer Ther. 2017 Sep;16(9):1739-1750
pubmed: 28572168
Foods. 2020 Dec 24;10(1):
pubmed: 33374455
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14788-93
pubmed: 25267614
Eur J Med Chem. 2021 Aug 5;220:113539
pubmed: 34034128
Ann Pharmacother. 2021 Sep;55(9):1172-1179
pubmed: 33348988
Nucleic Acids Res. 1997 Jun 15;25(12):2274-83
pubmed: 9173976
J Thorac Oncol. 2020 Apr;15(4):520-540
pubmed: 32018053
Genes Dev. 2006 Jun 1;20(11):1429-34
pubmed: 16751180
Nat Rev Cancer. 2017 Nov 10;17(12):765
pubmed: 29123245
Mol Cell. 2010 Jun 11;38(5):637-48
pubmed: 20541997
Transl Lung Cancer Res. 2016 Jun;5(3):288-300
pubmed: 27413711